The Fascinating Field of Obstetrics and Gynecology

Juntendo, which has a history dating back to the Edo era, has made major contributions to Japanʼs healthcare. In the field of obstetrics and gynecology, this school has provided various pioneering innovations and educational efforts including the development of a surgical technique for ovarian cystoma, implementation of the first cesarean section in Japan, and the introduction of painless delivery to this country. On the occasion of my retirement, I would like to highlight certain topics pertaining to clinical practice and research in obstetrics and gynecology during the past decade and how fascinating this field of medicine truly is.


Introduction
Juntendo, which has a history dating back to the Edo era, has made major contributions to Japanʼs healthcare. In the field of obstetrics and gynecology, this school has pioneered various innovations and educational efforts including the development of a surgical technique for ovarian cystoma, implementation of the first cesarean section in Japan, and the introduction of painless delivery to this country. On the occasion of my retirement, I would like to highlight certain topics pertaining to clinical practice and research in obstetrics and gynecology during the past decade and how truly fascinating this field of medicine is, hoping that many medical students will find this field interesting and choose it as their specialty.

History of Department of Obstetrics and Gynecology, Juntendo
Juntendo School was established in Sakura, Chiba Prefecture at present, in 1843. Later, in 1875, Juntendo Hospital was opened at its present location in Ochanomizu, Tokyo, laying the foundation for subsequent growth and prosperity. In 1910, the department of obstetrics and gynecology was established, and in 1946, Juntendo University was formed. It is a well-known fact that Jundo Ikoda, who studied at the Juntendo School, performed the first cesarean section in Japan in 1852. Jundo Ikoda and Kinpei Okabe performed the operation while referring to an obstetric textbook to save a pregnant woman who had suffered from dystocia for three days and nights in the days before anesthesia and sterilization were available, i. e., in the late Edo era. The operation was completed in about 1 hour, and the records of the operation and the postoperative course are available. Unfortunately, the baby died, but the mother recovered despite serious events such as postoperative infection and ileus, and lived out her natural life, reaching the age of 88. A second attempt at cesarean section was not made until 1879, when a foreign doctor in Yokohama performed the operation. Cesarean section began to be performed nationwide after 1897, being spread by doctors who returned from studying in Germany. Descendants of the first cesarean section patient are still living in the same area in Saitama Prefecture, where a monument commemorating the event now stands (Figure-1).
The first professor of obstetrics and gynecology was Dr. Tamaki Imai, and the professorship has now been passed to Dr. Satoru Takeda, who is the 9th department professor. At present, the department has over 130 members. The five Juntendoaffiliated hospitals, centering on Juntendo Hospital in Hongo, Tokyo, make concerted and dedicated efforts to engage in clinical practice, research and education. The department of obstetrics and gynecology is divided into three sections, namely, perinatal medicine, reproductive medicine, and gynecologic oncology, each of which pursues its unique areas of expertise and carries out interdisciplinary studies. Although the department targets diseases suffered by women only, it covers a broad range of ailments starting from those affecting the egg and fertilized egg periods to the fetal stage, neonatal stage, adolescence, maturation period, pregnancy, delivery and postpartum periods, meno-pausal period, and old age. Besides conducting tests, surgery and treatment related to the obstetrics sector, infertility and hormones, gynecologic tumors, postpartum depression, climacteric disorder, and osteoporosis, the departmentʼs clinical and research targets also include gynecological examinations as well as preventive medicine for osteoporosis and metabolic syndrome. It also offers forums focused on activities involving mental, societal and welfare issues, as well as those of health and hygiene, such as family planning consultation, schooling and counseling, and prevention of child abuse and domestic violence, among other important topics.
The department not only encompasses elements of emergency medicine, surgery, internal medicine and psychiatry, but also includes elements of preventive medicine as well as welfare and health and hygiene. As long as students have broad perspectives and a passionate desire for learning and exploration, they can enjoy studying at this department while receiving clinical and research training. The graduate school offers extensive educational and research courses, and has not only launched classes on obstetrics and gynecology but has also undertaken numerous joint projects with Juntendo Universityʼs clinical and basic departments.

Recent social and clinical issues in Japan
Perinatal care in Japan has made rapid progress in recent decades, leading to dramatic declines in maternal mortality, perinatal mortality, and neonatal mortality, achieving remarkable improvement of obstetrical outcomes. These results are the fruits of persistent efforts and dedication by our pioneering obstetricians and gynecologists. However, maternal mortality, which had steadily declined until 2007 (3.1/100,000 births), thereafter fluctuated annually, signaling a halt in any further decrements. This appears to be attributable to a variety of factors present in the past 20 years such as changes in the environment and social situation surrounding women including later marriage, increasing maternal age, greater numbers of high-risk pregnancies, the progress in infertility treatment, a shortage of obstetricians, and changes in the medical situation.
Womenʼ s ages at the first marriage are rising, Dr. Jundo Ikoda, who studied at the Juntendo School, performed the first cesarean section in Japan in 1852. He performed the operation while referring to an obstetric textbook to save a pregnant woman who had suffered from dystocia for three days and nights in Edo era. The monument has been erected at the place where they had performed the first cesarean section, to praise their great achievement.
showing a 5-year increase just in the past two decades. Now, the average marriage age is 30 years. Consequently, maternal age is rising in Japan, just as it is in Taiwan and Korea. Apparently, the trend towards later marriage is anticipated to increase at an ever greater rate in Japan. The total fertility rate in Japan is 1.42. A population of 270, 000 people, which would correspond to a medium-sized city, disappears in Japan every year. If this trend continues, we might see that 40 million people will have"disappeared"from Japan 50 years later.
As the age of pregnants becomes higher, there will be more complications of pregnancy and delivery. Consequently, C/S rates are increasing in Japan and have now reached 22% in this country. As the rate of cesarean section is increasing, those of placenta accrete, increta, percreta and cesarean scar pregnancy are also increasing. The more the C/S rate rises, the more often we are faced with obstetrical challenges such as massive bleeding.

Maternal suicide and perinatal mental healthcare
Abnormal maternal deaths in Tokyoʼs 23 wards were jointly examined with the Tokyo Medical Examinerʼ s Office to ascertain the actual state of maternal and late-maternal deaths from suicide during the 10 years from 2005 to 2014 1) . Among them, there were 63 suicides during the decade. There were 23 suicides during pregnancy. There were 40 suicides of women less than 1 year postpartum. Depression or schizophrenia was observed in 39% of suicide cases. Of the 40 postpartum women committing suicide, 60% had a psychiatric disorder. The most common disorder was postpartum depression, affecting 13 women (33%). As compared with the maternal suicide rates in the United Kingdom and Sweden, the suicide rate in the 23 wards of Tokyo is very high at 8.7 per 100,000 births, thus necessitating urgent measures 2) 3) .
Therefore, the present situation must urgently be ascertained and countermeasures need to be taken such as depression screening and improvement of the maternal health check-up system.

Influences of Japanese womenʼs preference for a thin physique
Our study revealed a trend toward decreased birth weights of Japanese neonates over these three decades, and this trend is ongoing. It is said that the preference for a thin physique among Japanese women began when the British model "Twiggy" visited Japan as the "mini-skirt queen" in 1967, and this trend has persisted. Factors influencing neonatal birth weight include the motherʼs physique type before pregnancy (low birth weight neonates from thin mothers and high birth weight neonates from obese mothers), weight gain in the mother during pregnancy, and glucose intolerance. Namely, the birth weight of the neonate becomes low if the mother is thin during pregnancy. As a result, the birth weight of neonates began to decrease starting around 1970, and this phenomenon, peculiar to Japan but not other industrialized countries, is attracting attention worldwide 4) . It has been said that Japan is, in effect, conducting a demonstration experiment of "the Dutch famine birth cohort study", which showed that infants born to mothers in a starvation state during pregnancy would be more likely to develop myocardial infarction or metabolic syndrome later in their lives. The disease concept of "developmental origins of health and diseases (DOHaD)", i.e., the concept that the nutritional environment in the womb may lead to future diseases including metabolic syndrome is currently in the process of being demonstrated, indicating the importance of nutritional management around the time of pregnancy 5) . Studies in this field have been more vigorous, producing various new findings.

Preeclampsia and metabolic syndrome
Pregnancy is a phenomenon in which a foreign substance, i.e., the fetus itself, which has half of its genes from its father, is present in the motherʼ s body; this is an unusual event unacceptable from the aspect of transplantation immunology. Although there is no doubt that some mechanism of immunological tolerance is working, the details of this mechanism remain unclear. In cases with metabolic syndrome, adipose cells are enlarged, and adipocytokines are produced and released, thereby causing various local or systemic changes, leading to the occurrence of hyperlipidemia, hypertension, diabetes mellitus, hyperuricemia, etc (Figure-2). Every woman, if she becomes pregnant, develops

Figure-2 Pregnant complications and metabolic syndrome in future
Every pregnant women develops hyperlipidemia, and women complicated with preeclampsia and gestational diabetes would develop hyperuricemia, or acute fatty liver, hypertension with endothelial damages due to fetal growth restriction, nephropathy, severe hypertension, eclampsia, and HELLP syndrome. These complications are similar to symptom of metabolic syndrome. The pathogenesis of pregnant complications and metabolic syndrome remains unclear but abnormal adipocytokine profile and excessive local production of cytokines were observed in both patients.

Figure-3 Site of action of COMT and role of 2-methoxyestradiol
Hypothetical models in the interaction of hyperhomocysteinemia and preeclampsia onset via COMT deficiency was proposed by Kanasaki K,et al 9) . Women with SNPs associated with low COMT enzymatic activity can exhibit severely suppressed COMT activity, leading to preeclampsia. hyperlipidemia, and some will also develop preeclampsia, gestational diabetes, hyperuricemia, or acute fatty liver, and endothelial damage may progress. However, when pregnancy ends, all of these features and symptoms generally normalize. Women who have developed hypertensive disorders of pregnancy or gestational diabetes are highly like to develop metabolic syndrome later in life even if their conditions normalize after the end of pregnancy. Pregnancy is a loading test, in a sense, for metabolic syndrome.
The pathogenesis of preeclampsia and gestational diabetes remains unclear but is certainly attracting considerable research attention. We have conducted collaborative research with Prof. Watada from the Department of Metabolism & Endocrinology, Juntendo University 6) 7) , and Associate Professor Kanasaki from the Department of Diabetology and Endocrinology, Kanazawa Medical University 8) 9) . We have approached elucidating the etiologic mechanisms underlying preeclampsia and metabolic syndrome, focusing on dysfunction of catechol-O-methyltransferase (COMT), a metabolic enzyme for estrogen and catecholamines. Estradiol is metabolized by COMT to produce 2-methoxyoes-tradiol (2-ME) (Figure-3) 9) . We have tested the hypothesis that if COMT functions poorly, 2-ME cannot be produced, and the subsequent pathway becomes non-functional, resulting in hypertension, abnormal glucose tolerance, etc (Figure-4). Several new findings have been obtained, arousing interest in the relationships of pregnancy with hypertension, hyperlipidemia, and abnormal glucose tolerance 10) 11) .

Estrogen-responsive genes and sports medicine
Estrogen-responsive genes are involved in various pathological conditions, and hormone-dependent tumors such as breast cancer and endometrial cancer have been studied from this perspective. We have examined the relationships between these genes and cancers in a collaborative study with Prof. Inoue and Prof. Ikeda from Saitama Medical University Research Center for Genomic Medicine. It has recently become apparent that an estrogenresponsive gene is related to the energy metabolism that occurs in muscle, and this issue is attracting considerable attention as a subject of research in sports medicine involving marathons 12) 13) . Estrogen is known to also be related to bone metabolism, and there has been rapid progress in research on this issue, in relation to the prevention of fatigue fracture and other injuries such as tendon rupture, particularly in view of the Tokyo Olympics to be held in 2020.

Colpopoiesis
Colpopoiesis in cases with vaginal hypoplasia or aplasia in Mayer-Rokitansky-Kuster-Hauser syndrome and androgen insensitivity syndrome is performed in a non-invasive manner or surgically. In the former case, the formation of the vagina takes time. On the other hand, surgical colpopoiesis by the modified McIndoe procedure using a free peritoneal graft or artificial dermis allows vaginal construction within a short period of time, but carries the risk of postoperative vaginal narrowing and scar formation. Colpopoiesis is also performed in the field of pediatric surgery for the treatment of persistent cloaca or in cases of sex reassignment surgery for gender identity disorder. However, some patients may suffer difficulty engaging in intercourse due to postoperative scars, and may thus consult a gynecologist.
The procedure of non-invasive vaginal construction (Frank method) using a vaginal dilator developed by Juntendo University allows vaginal construction in the outpatient setting (Figure-5). Therefore, patientsʼ preferences and satisfaction with this method are both high, providing a new understanding of the advantages of this method.

Assisted reproductive technology
Along with rapid advancements in assisted reproductive technology (ART), currently 2.7% of all neonates, or one out of 37 neonates, is born as a result of in vitro fertilization. Even men with azoospermia can become fathers if they have round cells in the testes 14) . Advances in technology and research in this field are increasing at a vigorous pace, and studies of oogonial stem cells, nucleus substitution, oocyte cryopreservation, etc., are progressing.

Current status of sex reassignment surgery
Gender identity disorder (GID)(currently called gender dysphoria) is a condition in which an individual feels immense discomfort with his or her biological sex. The first sex reassignment surgery (SRS) in Japan was performed in 1998 by a team at the Department of Plastic Surgery and the Department of Gynecology and Obstetrics at Saitama Medical Center, and we also participated in this team treatment effort. Thereafter, in 2008, the Act on Special Cases in Handling Gender Status for Persons with Gender Identity Disorder was amended to allow change of gender entry in the official family registry after gonadectomy. At present, about 800 individuals per year (a total of about 6,000 individuals to date) undergo SRS, and change their gender entries in order to live their lives comfortably. We believe that, although some biases still exist against this group of patients, we are certainly headed for a more mature and accepting society.

Figure-5 Development of vaginal dilator by Juntendo
We developed a new vaginal dilator and reported a conservative colpopoiesis by this dilator.